Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen capable of potently stimulating new blood vessel growth (angiogenesis). VEGF-165 and VEGF-121 are two different isoforms of the factor generated from the human VEGF gene by alternative splicing. VEGF-121 differs from VEGF 165 in that VEGF-121 does not bind. VEGF-165 has been shown to promote collateral-dependent blood flow in an animal model of peripheral arterial insufficiency, and has been proposed as a potential agent for the treatment of peripheral arterial disease. Since the heparin-binding region in VEGF-165 has been implicated as being involved in the inactivation and clearance of the factor in vivo, the long term goal of this project is to determine if VEGF-121, which lacks the heparin-binding sequences, shows advantages over VEGF-165 as a potential therapeutic agent. In Phase I of the project, recombinant versions of VEGF-121 and VEGF-165 will be generated and tested side-by-side in a rat model of peripheral arterial insufficiency. If VEGF-121 shows efficacy in these two in vivo experiments, then Phase II studies will be initiated that will in part compare VEGF-121 and VEGF-165 effects in dose-ranging experiments in vivo using various routes of drug administration.